This invention relates to peptides which are useful as therapeutic agents in the treatment of gastroenterological disorders.
Peptide YY (PYY) is a 36-residue peptide amide isolated originally from porcine intestine, and localized in the endocrine cells of the gastrointestinal tract and pancreas (Tatemoto et al. Proc. Natl. Acad. Sci. 79:2514, 1982). Peptide YY has N-terminal and C-terminal tyrosine amides; accordingly, these two tyrosines give PYY its name (Y represents the amino acid tyrosine in peptide nomenclature). In addition., PYY shares a number of central and peripheral regulatory roles with its homologous peptide Neuropeptide Y (NPY), which was originally isolated from porcine brain (Tatemoto, Proc. Natl. Acad. Sci. 79:5485, 1982). PYY is localized in intestinal cells; NPY, in contrast, is present in the submucous and myenteric neurons which innervate the mucosal and smooth muscle layers, respectively (Ekblad et al. Neuroscience 20:169, 1987). Both PYY and NPY are believed to inhibit gut motility and blood flow (Laburthe, Trends Endocrinol. Metab. 1:168, 1990), and they are also thought to attenuate basal (Cox et al. Br. J Pharmacol. 101:247, 1990; Cox et al. J. Physiol. 398:65, 1988; Cox et al. Peptides 12:323, 1991; Friel et al. Br. J. Pharmacol. 88:425, 1986) and secretagogue-induced intestinal secretion in rats (Lundberg et al. Proc. Natl. Acad. Sci USA 79:4471, 1982; Playford et al. Lancet 335:1555, 1990) and humans (Playford et al., supra), as well as stimulate net absorption (MacFadyen et al. Neuropeptides 7:219, 1986). Elevated plasma PYY levels have been reported in individuals suffering from several conditions that cause diarrhea (Adrian et al. Gastroenterology 89:1070, 1985). Taken together, these observations suggest that PYY and NPY are released into the circulation after a meal (Adrian et al. Gastroenterology 89:1070, 1985; Balasubramaniam et al. Neuropeptides 14:209, 1989), and, thus, may play a physiological role in regulating intestinal secretion and absorption, serving as natural inhibitors of diarrhea.
A high affinity PYY receptor system which exhibits a slightly higher affinity for PYY than NPY has been characterized in rat intestinal epithelia (Laburthe et al. Endocrinology 118:1910, 1986; Laburthe, Trends Endocrinol. Metab. supra) and shown to be negatively coupled to adenylate cyclase (Servin et al. Endocrinology 124:692, 1989). Consistently, PYY exhibited greater antisecretory potency than NPY in voltage clamped preparations of rat small intestine (Cox et al. J. Physiol. supra), while C-terminal fragments of NPY were found to be less effective in their antisecretory potency than PYY (Cox et al. Br. J. Pharmacol. supra). Structure-activity studies using several partial sequences have led to the identification of PYY(22-36) as the active site for interacting with intestinal PYY receptors (Balsubramaniam et al. Pept. Res. 1:32, 1988).
In addition, PYY has been implicated in a number of physiological activities including nutrient uptake (see, e.g., Bilcheik et al. Digestive Disease Week 506:623, 1993), cell proliferation (see, e.g., Laburthe, Trends Endocrinol. Metab. 1:168, 1990; Voisin et al. J. Biol. Chem, 1993), lipolysis (see, e.g., Valet et al., J. Clin. Invest. 85:291, 1990), and vasoconstriction (see, e.g., Lundberg et al., Proc. Natl. Acad. Sci., USA 79:4471, 1982).
The amino acid sequences of porcine and human PYY are as follows:
porcine PYY: YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY, (SEQ ID NO:1) PA0 human PYY: YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY. (SEQ ID NO:2) The amino acid sequences for dog PYY and for rat PYY are the same as that of porcine YYY. PA0 N-.alpha.-Ac-[Nle.sup.24,28,30, Trp.sup.27, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:3) PA0 N-.alpha.-Ac-[Nle.sup.24,28, Trp.sup.27,30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:4) PA0 N-.alpha.-Ac-[Nle.sup.24,28,30, Phe.sup.27, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:5) PA0 N-.alpha.-Ac-[Nle.sup.24,28, Phe.sup.27, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:6) PA0 N-.alpha.-Ac-[Trp.sup.30, .psi..sup.35/36 ]PYY(25-36)-NH.sub.2, (SEQ ID NO:7) PA0 N-.alpha.-Ac-[Trp.sup.30 ]PYY(25-36)-NH.sub.2, (SEQ ID NO:8) PA0 N-.alpha.-Ac-[Nle.sup.24,28, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2 (SEQ ID NO:9) and PA0 N-.alpha.-Ac-[Nle.sup.28, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:10) wherein .psi. in the foregoing formulas is --CH.sub.2 --NH--. The compound N-.alpha.-Ac-[Nle.sup.24,28, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2 (SEQ ID NO:9) shows unexpectedly enhanced activity as a more potent and longer lasting antisecretory agent when compared to PYY. PA0 N-.alpha.-R.sup.1 -[Nle.sup.24,28,30, Trp.sup.27, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, PA0 N-.alpha.-R.sup.1 -[Nle.sup.24,28, Trp.sup.27,30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, PA0 N-.alpha.-R.sup.1 -[Nle.sup.24,28,30, Phe.sup.27, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, PA0 N-.alpha.-R.sup.1 -[Nle.sup.24,28, Phe.sup.27, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, PA0 N-.alpha.-R.sup.1 -[Trp.sup.30, .psi..sup.35/36 ]PYY(25-36)-NH.sub.2, PA0 N-.alpha.-R.sup.1 -[Trp.sup.30 ]PYY(25-36)-NH.sub.2, PA0 N-.alpha.-R.sup.1 -[Nle.sup.24,28, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2 and PA0 N-.alpha.-R.sup.1 -[Nle.sup.28, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2 or a pharmaceutically-acceptable salt thereof, PA0 N-.alpha.-Ac-[Nle.sup.24,28,30, Trp.sup.27, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:3) PA0 N-.alpha.-Ac-[Nle.sup.24,28, Trp.sup.27,30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:4) PA0 N-.alpha.-Ac-[Nle.sup.24,28,30, Phe.sup.27, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:5) PA0 N-.alpha.-Ac-[Nle.sup.24,28, Phe.sup.27, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:6) PA0 N-.alpha.-Ac-[Trp.sup.30, .psi..sup.35/36 ]PYY(25-36)-NH.sub.2, (SEQ ID NO:7) PA0 N-.alpha.-Ac-[Trp.sup.30 ]PYY(25-36)-NH.sub.2 (SEQ ID NO:8) and PA0 N-.alpha.-Ac-[Nle.sup.28, Trp.sup.30, Nva.sup.31, .psi..sup.35/36 ]PYY(22-36)-NH.sub.2, (SEQ ID NO:10) or a pharmaceutically acceptable salt thereof. PA0 (I), (R.sup.1 R.sup.2)-A.sup.1 -A.sup.2 -A.sup.3 -A.sup.4 -A.sup.5 -A.sup.6 -A.sup.7 -A.sup.8 -A.sup.9 -A.sup.10 -R.sup.30, ##STR2## (III) (R.sup.1 R.sup.2)-[A.sup.5 -A.sup.6 -A.sup.7 -A.sup.8 -A.sup.9 -A.sup.10 ].sub.m R.sup.30, PA0 Asp=D=Aspartic Acid PA0 Ala=A=Alanine PA0 Arg=R=Arginine PA0 Asn=N=Asparagine PA0 Cys=C=Cysteine PA0 Gly=G=Glycine PA0 Glu=E=Glutamic Acid PA0 Gln=Q=Glutamine PA0 His=H=Histidine PA0 Ile=I=Isoleucine PA0 Leu=L=Leucine PA0 Lys=K=Lysine PA0 Met=M=Methionine PA0 Phe=F=Phenylalanine PA0 Pro=P=Proline PA0 Ser=S=Serine PA0 Thr=T=Threonine PA0 Trp=W=Tryptophan PA0 Tyr=Y=Tyrosine PA0 Val=V=Valine PA0 Fla=9-Fluorenylalanine PA0 Orn=Ornithine PA0 Nal=2-Napthylalanine PA0 Nle=Norleucine PA0 Nva=Norvaline PA0 Thi=2-Thienylalanine PA0 Pcp=4-Chlorophenylalanine PA0 Bth=3-Benzothienyalanine PA0 Bip=4,4'-Biphenylalanine PA0 Tic=Tetrahydroisoquinoline-3-carboxylic acid PA0 Tic-OH=7-Hydroxy-tetrahydroisoquinoline-3-carboxylic acid PA0 Aib=Aminoisobutyric acid PA0 Anb=.alpha.-Aminonormalbutyric acid PA0 Dip=2,2-Diphenylalanine PA0 Thz=4-Thiazolylalanine PA0 Dpr=1,2-Diamino propionic acid
U.S. Pat. No. 5,604,203, issued Feb. 18, 1997, to the present inventor generically discloses PYY analogs which encompass the compounds of this invention of the formula: